Corneal cross-linking (CXL) is an in-office eye procedure that strengthens the cornea if it's been weakened by keratoconus, other corneal disease, or (rarely) a complication of LASIK surgery. Alternative and brand names for the procedure include corneal cross-linking, corneal collagen cross-linking, C3-R, CCL and KXL.

The minimally invasive CXL procedure involves applying liquid riboflavin (vitamin B2) to the surface of the eye, followed by treatment with a controlled application of ultraviolet light, to eliminate corneal ectasia.

Epithelium-off CXL. In this type of cross-linking procedure, the thin outer layer (epithelium) of the cornea is removed to allow the liquid riboflavin to more easily penetrate the corneal tissue.

Epithelium-on CXL. In this procedure (also called transepithelial CXL), the protective corneal epithelium is left intact, requiring a longer riboflavin "loading" time.

Corneal cross-linking also can be combined with other procedures for keratoconus treatment. For example, combining CXL with implanting tiny arc-shaped corneal inserts called Intacs has been shown to help reshape and stabilize the cornea in more advanced cases of keratoconus.

Current Status Of CXL In The United States

In April 2016, the pharmaceutical and medical device company Avedro announced it received FDA approval for the company's KXL System that provides corneal collagen cross-linking for the treatment of progressive keratoconus. The approval includes Avedro's Photrexa Viscous and Photrexa, which are riboflavin solutions used with the KXL System during the procedure.

This is the first corneal collagen cross-linking system to gain the required regulatory approval to be performed by eye doctors in the United States for this sight-threatening condition.

Approval of Avedro's cross-linking system was based on the results of clinical trials that showed the Photrexa/KXL System halted and produced a mild reversal of the bulging of the cornea in patients with progressive keratoconus three to 12 months after the procedure. Patients who received a sham treatment for comparison purposes had a worsening of their keratoconus over the same period.

Prior to receiving FDA approval of the Photrexa/KXL System, Avedro announced in June 2015 that approximately 200,000 patient eyes outside the United States have been treated with the corneal cross-linking procedure.

Though Avedro's Photrexa/KXL System currently is the only FDA-approved cross-linking procedure for the treatment of progressive keratoconus in the U.S., if you have this condition or corneal ectasia following LASIK surgery, you also may be able to be treated with other cross-linking procedures that are not yet FDA approved.

This is possible due to something called "off-label use" — a term used to describe when a drug or medical device is used for a purpose for which it does not yet have regulatory approval. Off-label use of drugs and medical devices is legal in the United States, provided certain conditions are met and the patient is fully informed and agrees to the treatment.

Before agreeing to undergo an off-label procedure for the treatment of keratoconus or corneal ectasia, be sure to consult with your eye doctor so you fully understand the approval status, legality, risks, contraindications and possible side effects of the procedure.

Another option is to participate in a clinical trial designed to evaluate the safety and effectiveness of a new procedure for the treatment of keratoconus or corneal ectasia that is not yet FDA approved. If you are interested in participating in a study of this sort, visit our access page for the clinical trials operated by the National Institutes of Health, and type "corneal cross-linking" in the search box on the page to see if any trials are recruiting patients.

Who Are The Best Candidates For Corneal Cross-linking?

Corneal cross-linking is most effective if it can be performed before the cornea has become too irregular in shape or there is significant vision loss from keratoconus or other causes of corneal ectasia. If applied early, CXL typically will stabilize or even improve the shape of the cornea, resulting in better visual acuity and an improved ability to wear contact lenses.

Other potential applications of CXL include the treatment of corneal ulcers that are unresponsive to treatment with topical antibiotics. Studies also have found that corneal cross-linking can be effective for eradicating a variety of corneal infections.

Some surgeons have also reported reasonable results in improving the stability of the cornea in people who have undergone radial keratotomy, an incisional refractive procedure from the 1980s and 1990s. Cross-linking appears to work best for those who are experiencing daily fluctuations in their vision.

People who are considering vision correction procedures such as LASIK also might eventually be pre-treated with corneal cross-linking to strengthen the eye's surface before undergoing an excimer laserablation that reshapes the cornea.

What To Expect During And After A Corneal Cross-linking Procedure

During preliminary examinations, your eye doctor will measure the thickness of your cornea and make sure you are a good candidate for the procedure. You also will need to have a routine eye exam to assess your visual acuity and general eye health. And your doctor will perform mapping of your cornea (called corneal topography) to determine the level of your eye condition.

Layers of the cornea. Corneal cross-linking strengthens bonds in the stroma of the cornea, which is the layer from which tissue is removed during LASIK surgery.

The cross-linking procedure takes 60 to 90 minutes in most cases. If you are receiving epithelial-off cross-linking, your surgeon will place you in a reclining position and remove the epithelial layer from your cornea. Riboflavin eye drops will then be placed.

If you are receiving epithelial-on cross-linking, you are placed in a reclining position, and riboflavin drops are started. After enough time has passed (depending on the technique), the surgeon will evaluate your eye to ensure that the cornea has sufficient riboflavin present.

The corneal thickness will be checked, and then the UV light will be applied for up to 30 minutes.

In some cases, a bandage contact lens will be placed. Topical antibiotic and anti-inflammatory drops will be prescribed.

With both epithelial-off and epithelial-on CXL, studies have found that 99 percent of patients will remain stable or achieve improvement in the corneal shape, which is highly significant for people with progressive keratoconus that otherwise might lead to severe vision loss.

And though corneal cross-linking may cause some initial eye irritation, the surface of the eye and the tear film appear to fully recover within several weeks. In a recent study designed to investigate potential alterations of the eye's surface and tear film parameters three months after CXL in progressive keratoconus patients, no adverse effects on the ocular surface and tear function (which are important for visual quality) were found.

Epithelium-Off vs. Epithelium-On CXL

One of the big questions is whether epithelium-on CXL (transepithelial CXL) can provide similar results to cross-linking procedures where the epithelium has been removed (epi-off CXL).

One recent study that compared the effectiveness of the two procedures for the treatment of 36 eyes of 27 patients ages 12 to 18 years who were diagnosed with progressive keratoconus found that at 24 months after treatment, 94.4 percent of eyes in the epi-off CXL group (18 eyes) either showed less keratoconus or had no worsening of the disease, whereas only 66.6 percent of eyes in the epi-on CXL group (18 eyes) improved or stabilized. The study authors concluded the epi-on CXL procedure was only 70 percent as effective as epi-off CXL in terms of its ability to stop the progression of keratoconus.

In Europe, a special riboflavin formulation (Ricrolin TE) has been developed that helps riboflavin penetrate the corneal epithelium more easily to facilitate epithelium-on CXL. And in the United States, other researchers have reported visual results from epi-on CXL that are similar to those of epi-off CXL.

Advantages of epithelium-on CXL include reduced risk of infection, less corneal haze and fewer delays in epithelial healing. And though some studies show outcomes with epithelial-off CXL tend to be significantly better in younger candidates than in people older than age 35, this difference does not appear to be an issue with transepithelial CXL. Epithelium-on CXL also allows for quicker visual recovery and less discomfort.

Keratoconus Treatment

After undergoing corneal collagen cross-linking and implantation of an ICL, Steve Holcomb could see so well that he led his team to an Olympic gold medal victory in bobsledding. (Video: NBC Nightly News)

Novel Eye Procedure Helps Win Olympic Gold Medal

U.S. Olympic bobsledding champion Steve Holcomb overcame a heartbreaking diagnosis of legal blindness that threatened to rob him forever of his lifelong dream of winning an Olympic gold medal.

Holcomb had progressive keratoconus, a thinning of his cornea that caused irregularities on his eye's surface to continually worsen.

By 2007, his vision had degraded so rapidly that numerous ophthalmologists told Holcomb his only hope for restoring at least some sight was to undergo a corneal transplant. And this meant Holcomb could never again participate in the jarring sport of bobsledding, because his eyes could be injured.

He and Olympic team members searched for another answer and discovered that Beverly Hills ophthalmologist Brian Boxer Wachler had been performing a procedure that might save his eyesight.

Holcomb received an application of liquid riboflavin that was then activated by UV-A light. This was the transepithelial (epithelium-on) type of corneal cross-linking. Dr. Boxer Wachler followed up with implantation of a special contact lens (ICL), which further improved Holcomb's vision.

In February 2010, at the Winter Olympics in Vancouver, Holcomb and teammates rode a bobsled nicknamed the "Night Train" down icy slopes straight to an Olympic gold medal — the first in bobsledding for the United States in 62 years. (Watch video.)

"His story is one of triumph over adversity," said Dr. Boxer Wachler, who also is a member of AllAboutVision.com's editorial board.

Dr. Boxer Wachler admits he had some harsh critics in the early years of using the procedure off label. And as far as he knows, he was the only U.S. eye surgeon using the treatment when he first developed the technique in 2003.

"Someone once told me that a pioneer is someone who goes out into the wilderness, and then comes back with arrows in his back," Dr. Boxer Wachler joked. But he saw the results and believed in what he was doing.

Critics have also disputed his argument that the epithelium should be left on the corneal surface to greatly reduce pain, accelerate healing, protect against infection and reduce the possibility of complications such as corneal haze.

While in some studies transepithelial crosslinking produced less effective results than techniques involving removal of the epithelium, Boxer Wachler said that the solution he uses loosens the eye's surface enough to allow penetration by the riboflavin. He said he also uses a more liquid consistency of the riboflavin than what was tested in other studies, to make sure the substance penetrates the cornea.

William Trattler, MD, a Miami ophthalmologist and the reviewer of this article, is participating in clinical trials that explore both methods of corneal cross-linking. He said the method Boxer Wachler uses appears to produce identical results to the epithelium-off method of CXL while significantly improving patient comfort and safety.

"My position on the epithelium-on method is that it is more comfortable and has a more rapid return of vision, while producing similar visual results," Trattler said. "Plus, it is minimally invasive." — M.H.

Cost Of Corneal Cross-Linking

The cost of a corneal cross-linking procedure for keratoconus or corneal ectasia can range from $2,500 to $4,000 per eye.

Some of this cost may be covered by your health insurance policy. Ask your eye doctor or insurance company for assistance in determining what your total out-of-pocket expense for the procedure will be. AAV

Collagen corneal cross-linking. Presentation by Ramon Naranjo-Tackman, MD, at Cornea Day 2011 sponsored by the American Society of Cataract and Refractive Surgery. March 2011.

Corneal collagen crosslinking: promises and problems. British Journal of Ophthalmology. December 2010.

About the Reviewer: William Trattler, MD, is a board-certified ophthalmologist specializing in refractive, corneal and cataract eye surgery at the Center for Excellence in Eye Care  a private practice in Miami that treats a wide range of vision disorders and provides laser vision correction. More about Dr. Trattler